IP Indian Journal of Clinical and Experimental Dermatology 2020;6(4):391–396

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IP Indian Journal of Clinical and Experimental Dermatology

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Original Research Article

Effectiveness and safety of combination of Itraconazole and Amorolfine inmanagement of patients with recalcitrant multi-site dermatophytosis who failedprevious combination antifungal therapy

Vishalakshi Vishwanath1, Pradnya Londhe1, Dakshata Tare1, Gaurav Deshmukh2,*,Dhiraj Dhoot2, Hanmant Barkate3

1Dept. of Dermatology, Rajiv Gandhi Medical College & CSM Hospital, Kalwa, Thane Municipal Corporation, Maharashtra,India2Global Medical Affairs (IF), Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India3Global Medical Affairs (IF & MEA), Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India

A R T I C L E I N F O

Article history:Received 17-11-2020Accepted 19-11-2020Available online 05-12-2020

Keywords:ItraconazoleAmorolfineDermatophytosisCombination Therapy

A B S T R A C T

Introduction: There is alarming rise in cases of dermatophytosis in India. Standard treatmentrecommendations are no longer working. Combination of topical and systemic antifungal drugs is oneof the most frequently used treatment strategy.Materials and Methods: This was an open label, prospective, interventional, non-comparative study.Effectiveness endpoints were percentage of patients achieving complete cure, clinical cure and mycologicalcure at the end of the treatment period from baseline. Safety was assessed by analyzing the AEs andmonitoring of liver function tests.Results: 66 patients were included in the study. 75.75%, 86.36% and 81.8% patients achieved completecure, clinical cure and mycological cure respectively at the end of the study period. There was improvementin each symptom during study duration as observed during each follow up visit on week 2, 4 and 6. Total of10.60% reported 1 or more drug related AE. Nausea was most common side effect followed by vomiting,headache and edema of face. All the AEs were mild in nature and resolved during study.Conclusion: To conclude the result of this study shows that the combination therapy of oral itraconazoleand topical amorolfine represents an improved treatment strategy for patients with recalcitrant multisitetinea infections.

© This is an open access article distributed under the terms of the Creative Commons AttributionLicense (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, andreproduction in any medium, provided the original author and source are credited.

1. Introduction

Currently, there is alarming rise in cases of dermatophytosisin India. In current scenario standard treatmentrecommendations from literature are no longer validor even realistic.1 This has led to practice of experience-based treatment strategies by majority of dermatologistssuch as use of higher dose of oral antifungals, prolongedduration of therapy, use of drugs not approved in treatmentof dermatophytosis.1,2

* Corresponding author.E-mail address: drgaurav0@gmail.com (G. Deshmukh).

Combination of topical and systemic antifungal drugsis one of the most frequently used treatment strategy bydermatologists for management of dermatophytosis. It isproving to be more effective than either systemic or topicalantifungal alone because of pharmacokinetic advantagesof combination therapy. However, there are no definitivecomparative studies on combination of systemic and topicalantifungal treatment and this strategy is more of hit andtrial rather than evidence-based approach.2 Thus despiteusing combination therapy many patients shows recurrenceof dermatophytosis. In various studies itraconazole andamorolfine have shown synergistic activity when used in

https://doi.org/10.18231/j.ijced.2020.0762581-4710/© 2020 Innovative Publication, All rights reserved. 391

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combination against dermatophytes.3–5

Keeping these scenarios in mind we conducted thisstudy of combination of Itraconazole and Amorolfinebecause of their proven synergistic activity in managementof dermatophytosis in patients who failed to respondto previous combination antifungal therapy or who havedeveloped recurrence despite treatment with combinationtherapy.

2. Materials and Methods

2.1. Study design

This was an open label, prospective, interventional, non-comparative, single arm and single center study. The studyduration was 6 months from November 2018 to April 2019.The study was approved by Institutional Clinical EthicsCommittee (ICEC) and conducted in accordance with theDeclaration of Helsinki. The present study is registered atCTRI database (CTRI/2019/04/018560).

2.2. Patients Selection Criteria

Patients fulfilling following criteria were included in thestudy

1. Both male and female patients more than 18 years ofage

2. Patients with multi-site tinea infection confirmed bypositive KOH microscopy (Multisite tinea infectionwas defined as the patients with more than lesions attwo different anatomical sites on their body e.g. tineacorporis et cruris meaning patients with tinea lesionson his/her trunk and groin area.)

3. Patients who failed to respond to previouscombination therapy or who showed recurrencedespite treatment with combination therapy ofsystemic and topical antifungal agents.

Treatment failure was defined as lack of response after4 weeks of combination therapy with systemic andtopical antifungal drugs. Recurrence was defined as thereappearance of lesions within 6 weeks after completionof the treatment. Combination therapy was defined assimultaneous use of systemic and topical antifungal drugsfor management of tinea infections.

Patients with following characteristics were excludedfrom the study.

1. Patients who received combination of itraconazole andamorolfine for management of tinea infection

2. Patients with single site lesions, concomitant bacterialskin infection, other dermatological conditions likedermatitis, psoriasis, etc.

3. Patients with history of liver or cardiac disease werealso excluded from the study

4. Patients receiving immunosuppressive medications orsuffering from immunosuppressive illnesses were alsoexcluded from the study.

2.3. Visits and follow-ups

After the initial visit, follow-up visits were carried out at2, 4 and 6 weeks. Those patients who were already takingitraconazole at screening visit were given 1 week washout period. Each patient was treated with oral Itraconazole100mg twice daily for 4 weeks and topical Amorolfine0.25% applied twice daily for 6 weeks. During each visitpatients were examined for their improvement of symptoms.KOH examination was performed at initial visit and after6 weeks. Monitoring of liver function tests was carried foreach patient before and during treatment period.

2.4. Effectiveness Assessment

2.4.1. Primary effectiveness end pointPrimary effectiveness endpoint was percentage of patientsachieving complete cure at the end of the treatment periodfrom baseline. Complete cure was defined as the patientsachieving both clinical cure and mycological cure at the endof treatment.

2.4.2. Secondary effectiveness end pointSecondary effectiveness end points were

1. Percentage of patients achieving clinical cure at theend of treatment period. Clinical cure was defined asclear or almost clear symptoms at the end of treatment.

2. Percentage of patients achieving mycological cureat the end of treatment period. Mycological curewas defined as negative microscopy under potassiumhydroxide (KOH) examination at the end of therapy.

3. Improvement in each symptom from baseline in eachvisit.

For effectiveness assessment each patient was evaluatedfor clinical and mycological improvement. Clinicalimprovement was assessed by evaluating the improvementin common symptoms of dermatophytosis (scaling,erythema, itching and incrustation) on five-point scale (0 –4) with 0 being the complete resolution of symptom while 4being the severe symptom. Mycological improvement wasassessed by examining 10% KOH mount of skin scrapingunder microscope before and after treatment.

2.5. Safety Assessment

Safety assessment was done by analyzing all the AEsreported by the patients during treatment and by monitoringthe liver function tests for evaluating the effect ofitraconazole on liver.

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2.6. Data analysis

Descriptive statistics were used to summarize effectivenessand safety endpoints using GraphPad Prism version 8(San Diego, California: GraphPad Software Inc., 20057). Pvalues ≤0.05 were considered statistically significant.

3. Results

Among 100 patients screened, 80 patients who fulfilledthe inclusion criteria were included in the study. 66patients completed the follow up period of 8 weeks andwere considered for final analysis. 4 patients developedreappearance of lesions during treatment period anddiscontinued the therapy. 10 patients were lost to follow up.

The average age of the patients was 35.68 ± 11.32years. Out of 66 patients, 36 were male (54.5%) while30 were females (45.5%). Tinea corporis et cruris wasmost common infection (n =32, 48.4%). The most commonprevious therapy was combination oral itraconazole plustopical luliconazole used by 50% (n = 33) of patients. Thedemographic characteristics of the patients are described inTable 1.

Table 1: Baseline Demographic Details (n = 66)

VariableAge (Mean, SD) 35.68 ± 11.32

yearsSex No. (%)• Male 36 (54.5%)• Females 30 (45.5%)Type of Infection• Tinea corporis et cruris 32 (48.4%)• Tinea corporis et cruris et pedis 16 (24.4%)• Tinea corporis et Cruris et faciei 6 (9.09%)• Tinea corporis et cruris et pedis et facie 6 (9.09%)• Tinea cruris et corporis et barbie 4 (6.06%)• Tinea mannum et cruris et corporis 2 (3.03%)Previous Therap• Cap. Itraconazole 100mg BD plusLuliconazole 1% BD

33 (50%)

• Cap. Itraconazole 100mg BD plusSertaconazole 2% BD

17 (25.75%)

• Cap. Itraconazole 100mg BD plusClotrimazole 2% BD

10 (15.15%)

• T. Terbinafine 250mg BD plusLuliconazole 1% BD

4 (6.06%)

• T. Griseofulvin 500mg BD plusClotrimazole 2% BD

2 (3.03%)

Baseline Symptom Severity (mean, SD)• Erythema 2.76 ± 0.62• Scaling 2.55 ± 0.73• Pruritus 3.61 ± 0.52• Incrustation 1.1 ± 0.81

3.1. Effectiveness Analysis

3.1.1. Complete cureOut of 66 patients analyzed, 75.75% (n = 50) patientsachieved complete cure at the end of treatment period.(Figures 1, 2, 3 and 4) None of the patient who achievedcomplete cure developed any sign of worsening of symptomafter 2 weeks of completion of therapy as confirmed bytelephonic follow up.

Fig. 1: Effectiveness Assessment of combination of Itraconazoleand Amorolfine

Fig. 2: A, B- Extensive Inflammatory tinea Corporis et cruris witherythema and pustules seen; C, D- Complete resolution of lesionsseen at day 42

3.1.2. Mycological CureAt the end of treatment period of 6 weeks, 81.8% (n = 54)patients achieved mycological cure i.e. negative microscopyat the end of treatment period. (Figure 1)

3.1.3. Clinical Cure and total Symptom scoreAfter 6 weeks of antifungal therapy, 86.36% (n = 57)patients showed complete resolution of their symptoms oferythema, scaling, pruritus and incrustation thus achieving

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Fig. 3: A, B- Extensive Tinea Corporis et faciei with irritantcontact dermatitis; C, D- Complete clearance of lesions in patientwith multiple site involvement after 1 month of treatment

Fig. 4: A- Patient with Tinea Incognito; B- Good clearance of thelesions at end of 1 month

clinical cure (Figure 2). There was improvement in eachsymptom during study duration as observed during eachfollow up visit on week 2, 4 and 6. Mean baseline erythemascore was 2.76 ± 0.62 at the start of study which wassignificantly decreased to 0.13 ± 0.33 (p < 0.0001) after 6weeks. There was significant improvement in scaling of thepatients from baseline at the end of therapy (2.55 ± 0.73 vs.0.23 ± 0.55; p < 0.0001). Similarly, there was significantdecrease in pruritus (3.61 ± 0.52 vs. 0.34 ± 0.66; p <0.0001) and incrustation (1.1 ± 0.81 vs. 0.08 ± 0.28; p <0.0001) from baseline at the end of therapy. (Figure 5)

3.2. Safety analysis

Out of 66 patients, 10.60% (n = 7) reported 1 or more drugrelated AE. Nausea was most common side effect reportedby 9.09% (n = 6) patients followed by vomiting (6.06%, n =4); headache (4.54%, n = 3) and edema of face (1.51%, n =

Fig. 5: Improvement in each symptom

1). All the AEs were mild in nature, appeared during initial2 weeks of therapy and resolved during study, none of thepatient discontinued the therapy because of AEs. (Figure 6)

Fig. 6: Adverse events reported by the patients

Liver function of all the patient was evaluated byanalyzing the levels of Serum glutamic oxaloacetictransaminase (SGOT) and Serum glutamic pyruvictransaminase (SGPT) before initiation of itraconazole, atweek 2 and at week 4 after completion of itraconazoletherapy. The baseline SGOT & SGPT levels were 19.97± 7.34 and 19.86 ± 11.40 respectively. After 2 weeks ofitraconazole therapy there was no significant change inSGOT and SGPT levels (19.06 ± 7.44 and 18.62 ± 10.70respectively, p = 0.1). At week 4 similar results were seenwith no significant change in SGOT and SGPT levels (19.76± 7.40 and 19.02 ± 11.50 respectively, p = 0.1).

4. Discussion

Based on initial studies and recommendations topicalantifungals are first line drugs in management of tineainfections. However, in patients with large lesions ormultisite tinea infections only topical therapy fails to clearlesions leading to treatment failures. Systemic therapy isrecommended in such patients where topical therapy fails.6

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Oral itraconazole is drug of first choice in management oftinea infections in current scenario in India. Various earlierstudies have shown variable but appreciable cure ratesfor dermatophytosis in the range of 72.7–96.6% followingitraconazole therapy.7–11 However recently lower cure rateswith itraconazole have been reported. Sharma et al in theirstudy reported only 50% cure rate with 3 weeks 200mg/dayitraconazole therapy.12 Similar decrease in clinical efficacyof amorolfine is evident from recent report by Das et al whoreported only 26.09% complete cure rate with amorolfinewhich was lower as compared to previous studies showingvariable cure rates of 80 – 90%.13

Hence combination therapy seems more useful inmanagement of patients with multi-site tinea infections.Sahoo et al and Murlidhar et al in the comprehensivereviews recommended the use of combination of topicaland systemic antifungals in management of patients withlarge lesions or recalcitrant tinea infections. Authorscommented that while using combination therapy drugsfrom two different class should be used for wider coverage,synergistic or additive action and to reduce the chance ofresistance.6,14

In our study 90.0% (n = 60) patients were previouslytreated with combination of oral and topical azole. Theuse of combination of same class of drugs might be oneof the reasons of treatment failure seen in these patients.Various in-vitro studies have demonstrated mixed results ofantagonism or indifference with combination of two drugsacting at same target.15,16

Synergistic activity of combination of itraconazole andamorolfine has been shown in some in-vitro studies.3,4 Inhumans the improved activity of combination has beenshown in patients with onychomycosis where combinationtherapy was better than monotherapy with itraconazole.5

Theoretically sequential inhibition of 14 α demethylaseby itraconazole and inhibition of delta-14-reductase anddelta-7, 8-isomerase by amorolfine may result in morecomplete suppression of ergosterol synthesis resulting betterantifungal activity.

In present study complete cure rate of 75.75% wasmore compared to monotherapy with itraconazole (50%)or amorolfine (26.09%) alone. Mycological cure rate in ourstudy was 81.8% which is higher than the mycological curerate reported for monotherapy with either drug. Das et alin their study reported mycological cure rate of 80% whileBanerjee et al reported mycological cure rate of 78.9% inpatients treated with amorolfine.13,17 Similarly Sharma etal in their study reported mycological cure rate of 50%for itraconazole monotherapy.12 This clearly indicates thatthe combination therapy with amorolfine and itraconazoleis better than either therapy alone in management ofrecalcitrant multisite tinea infection.

Similarly, the clinical cure rate in our study was betterthan the clinical cure reported for either drug alone. In ourstudy 86.36% patients achieved clinical cure rate compared

to clinical cure rate of 50% reported by Sharma et al in theirstudy for itraconazole monotherapy.12

With regards to safety, only 10.60% patients reported1 or more AE in our study. All the adverse effects wereof mild to moderate severity and none of the patientsrequired discontinuation of therapy. None of the patient inour study reported any derangement of liver function duringtreatment period. Adherence to treatment was excellent inall the patients. These results are in accordance with thesafety profile of both amorolfine and itraconazole reportedin earlier studies.7–11

5. Limitations

Limitations of our study include the small population. Thefungal culture and sensitivity could not be done due to non-feasibility.

6. Conclusion

To our knowledge this is the first Indian study providingthe evidence that the commonly used treatment strategyof combination of topical and systemic antifungal drugsis efficacious and safe in management of multi-site tineainfections. This study also proves that use of combinationof two different class of antifungal drugs is associated withimproved antifungal activity.

To conclude the result of this study shows that thecombination therapy of oral itraconazole and topicalamorolfine represents an improved treatment strategy forpatients with recalcitrant multisite tinea infections whofailed previous combination antifungal therapy.

7. Source of Funding

No financial support was received for the work within thismanuscript.

8. Conflict of Interest

The authors declare they have no conflict of interest.

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Author biography

Vishalakshi Vishwanath, Professor and Head

Pradnya Londhe, Associate Professor

Dakshata Tare, Assistant Professor

Gaurav Deshmukh, Manager

Dhiraj Dhoot, Senior Manager

Hanmant Barkate, Vice President

Cite this article: Vishwanath V, Londhe P, Tare D, Deshmukh G, DhootD, Barkate H. Effectiveness and safety of combination of Itraconazoleand Amorolfine in management of patients with recalcitrant multi-sitedermatophytosis who failed previous combination antifungal therapy. IPIndian J Clin Exp Dermatol 2020;6(4):391-396.